The present invention relates to gel compositions which comprise gel-forming moieties which bind to one another to form a gel. The binding of the gel-forming moieties is dependent on the level of a specific analyte and may be reversible. Such gels find use in monitoring the level of the analyte in a sample and delivering drugs in response to abnormal levels of the analyte.
In the prior art, WO 93/13803 discloses a gel which, in one embodiment, comprises dextran and concanavalin A (ConA). Terminal glucose residues of dextran bind to ConA, resulting in the formation of a higher viscosity gel. Reversal of this binding occurs when free glucose competes with the dextran glucose residues for binding to ConA. Thus, the gel is sensitive to the amount of free glucose with which it is brought into contact. As such, the gel can be used as a drug delivery system using an anti-hyperglycaemic drug such as insulin. In normal levels of glucose, dextran binds ConA and the gel retains the insulin therein. However, when the level of glucose rises, the degree of binding falls, releasing the insulin. In a physiological situation, the release of insulin will result in the level of glucose falling and the degree of binding will increase, thereby preventing release of further insulin. Thus, the drug delivery system forms a “closed loop” system which has the same effect as a normally-functioning pancreas, with insulin being released when required (when glucose causes the gel to undergo gel-sol transition) and retained when not required (when the lack of glucose causes the gel to undergo sol-gel transition).
Similar gels are disclosed in Obaidat & Park, Biomaterials 18 (11 1997): 801-806; Obaidat & Park, Pharmaceutical Research 12 (9 SUPPL 1995); Obaidat & Park, Pharmaceutical Research 13 (7 1996): 989-995; and Valuev, et al, Vysokomolekulyarnye Soedineniya Seriya A & Seriya B (1997): 751-754.
A gel of this type is disclosed for use as a glucose sensor in DE-A-4203466. The gel is located in a semi-permeable tube such that the change in viscosity of the gel resulting from the reversible gel-sol change causes the gel surface to respond to an oscillation signal. The degree of response depends on the viscosity of the gel and hence the concentration of glucose. Later work describes the response of such a gel to glucose as measured by surface plasmon resonance (SPR) to measure the kinetics of the response rather than the viscosity itself (Ballerstadt & Schultz, Sensors and Actuators B Chemical, (1998), 46: 557-567). Rather than producing a gel, a lectin was immobilised on a surface and the displacement of fluorescent labelled lectin was measured with laser optics. Thus, this later work did not use the change in viscosity as a measure of glucose levels. Similarly, DE-A-4034565 describes the measurement of radioactive lectin from cross-linked dextran beads.
Finally, WO99/48419 describes the use of a viscosity-sensitive chip to measure the change of viscosity of a reversible gel (specifically a Ficoll-ConA gel) to determine the level of glucose in a sample to be analysed.
A problem of gels of this type is that they are water-miscible and hence are prone to dispersal. This problem becomes particularly acute if they are used in vivo to detect a particular analyte, because the components of the gel could cause an unwanted immune reaction: indeed, ConA is mitogenic. For this reason, the gels may be enclosed by a semi-permeable membrane which will allow passage of the analyte into contact with the gel. However, in order for the gel to react to changed levels of analyte within a reasonable time, the analyte must be able to pass quickly through the semi-permeable membrane. In addition, in those situations where a drug is to be released, the membrane must allow quick release. To ensure such quick passage, the membrane needs to have relatively large openings and/or be relatively thin, with the result that the components of the gel can leach through the semi-permeable membrane. For example, a gel of the type described in WO 93/13803 is water-miscible and must be confined in a small pore membrane to prevent rapid dispersal of the gel-forming components, especially in the sol form induced by raised levels of glucose. However, pore sizes (e.g. 0.1 μm) which are not rate-limiting for release of the 36 kD insulin hexamer still allow the 10 kD ConA tetramer and, to a lesser extent, dextran to escape.
It is therefore desirable to produce a gel of the type described above which is less prone to dispersal.
According to the present invention, there is provided a gel composition comprising first and second gel-forming moieties which bind reversibly to one another to form a gel, wherein said binding is sensitive to the level of an analyte, and either or both of the gel-forming moieties are attached to cross-linked particulate entities such that the interstices between the entities allow gel-sol and sol-gel transformation, and yet are not so small that the analyte cannot diffuse therethrough.